MHC class I polypeptide–related sequence A

MHC class I polypeptide–related sequence A (MICA) is a highly polymorphic cell surface glycoprotein encoded by the MICA gene located within MHC locus.[3] MICA is related to MHC class I and it has similar domain structure, however, it is not associated with β2-microglobulin nor binds peptides as conventional MHC class I molecules do.[4] MICA rather functions as a stress-induced ligand (as a danger signal) for integral membrane protein receptor NKG2D ("natural-killer group 2, member D"). MICA is broadly recognized by NK cells, γδ T cells, and CD8⁺ αβ T cells which carry NKG2D receptor on their cell surface and which are activated via this interaction.[5]

MICA
Available structures PDB Human UniProt search: PDBe RCSB List of PDB id codes 1B3J, 1HYR
Identifiers
Aliases	MICA, MIC-A, PERB11.1, MHC class I polypeptide-related sequence A, MHC class I chain–related protein A, MHC class I polypeptide–related protein A
External IDs	OMIM: 600169 GeneCards: MICA
Gene location (Human) Chr. Chromosome 6 (human)[1] Band 6p21.33 Start 31,399,784 bp[1] End 31,415,315 bp[1]
RNA expression pattern More reference expression data
Gene ontology Molecular function • beta-2-microglobulin binding • GO:0001948 protein binding • natural killer cell lectin-like receptor binding Cellular component • cytoplasm • integral component of membrane • membrane • cell membrane • integral component of plasma membrane • cell surface • extracellular • external side of plasma membrane Biological process • cytolysis • adaptive immune response • negative regulation of natural killer cell activation • immune system process • gamma-delta T cell activation • response to heat • immune response to tumor cell • cellular response to DNA damage stimulus • defense response to bacterium • defense response to virus • regulation of immune response • negative regulation of natural killer cell mediated cytotoxicity • GO:0022415 viral process • T cell mediated cytotoxicity • natural killer cell mediated cytotoxicity • immune response • natural killer cell activation • susceptibility to natural killer cell mediated cytotoxicity Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	100507436	n/a
Ensembl	ENSG00000231225 ENSG00000235233 ENSG00000204520 ENSG00000183214 ENSG00000233051 n/a	n/a
UniProt	Q29983	n/a
RefSeq (mRNA)	NM_001289154 NM_000247 NM_001177519 NM_001289152 NM_001289153	n/a
RefSeq (protein)	NP_000238 NP_001170990 NP_001276081 NP_001276082 NP_001276083	n/a
Location (UCSC)	Chr 6: 31.4 – 31.42 Mb	n/a
PubMed search	[2]	n/a
Wikidata
View/Edit Human

Structure

The MICA gene is highly polymorphic in humans with more than 50 defined alleles. It is located on chromosome 6 and the protein is expressed in two isoforms formed by alternative splicing: MICA1 and MICA2 which is lacking exon 3.[6] MICA contains external α1α2α3 domain, transmembrane segment and C-terminal cytoplasmic tail. It binds in a form of monomer to a KLRK1/NKG2D homodimer.[7]

There are no orthologs of the MICA in mice species.[8]

Expression

Expression of MICA can be upregulated by heat shock[4] or by exposure of the cells to DNA damaging conditions (for example ionizing radiation, chromatin-modifying interventions and inhibitors of DNA replication). The expression can be as well affected by some infectious agents such as human cytomegalovirus (HCMV), human adenovirus 5, M. tuberculosis, diarrheagenic E.coli,[7] or human papillomavirus (HPV).[9]

In the negative regulation of MICA expression, microRNA-183 plays an important. It downregulates its expression after exposure to transforming growth factor beta (TGFβ).[10]

In normal tissue, MICA is expressed mainly intracellularly with just a small fraction appearing on the surface of some epithelial cells.[11] There is no expression of MICA in the cells of the central nervous system (CNS).[7]

Function

MICA plays the role of stress-induced self-antigen and serves as a ligand for the KLRK1/NKG2D killer activation receptor.[12] Engagement of NKG2D-MICA results in activation of effector cytolytic responses of T cells and NK cells against epithelial tumor cells (or other stressed cells) expressing MICA on their surface.[5]

As a defense mechanism, tumor cells are able to avoid recognition of MICA by the immune system through proteolytic shedding of the surface expressed protein by the cooperation of disulfide isomerase (ERp5) and ADAM (a disintegrin and metalloproteinase) and MMP (matrix metalloproteinase) proteases targeting membrane-proximal α3 domain.[13] High levels of MICA in the serum of tumor patients are positively related to tumor size and poor prognosis.[14]

Variations in the MICA gene are also associated with susceptibility to psoriasis 1 and psoriatic arthritis and MICA-specific antibodies or its shedding are involved in the monoclonal gammopathy of undetermined significance´s (MGUS) progression to multiple myeloma.[7]

See also

• MHC class I
• Major histocompatibility complex
• MHC class I polypeptide-related sequence B

References

1. ENSG00000235233, ENSG00000204520, ENSG00000183214, ENSG00000233051 GRCh38: Ensembl release 89: ENSG00000231225, ENSG00000235233, ENSG00000204520, ENSG00000183214, ENSG00000233051 - Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. Bahram S, Bresnahan M, Geraghty DE, Spies T (July 1994). "A second lineage of mammalian major histocompatibility complex class I genes". Proceedings of the National Academy of Sciences of the United States of America. 91 (14): 6259–63. doi:10.1073/pnas.91.14.6259. PMC 44180. PMID 8022771.
4. Groh V, Bahram S, Bauer S, Herman A, Beauchamp M, Spies T (October 1996). "Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium". Proceedings of the National Academy of Sciences of the United States of America. 93 (22): 12445–50. doi:10.1073/pnas.93.22.12445. PMC 38011. PMID 8901601.
5. Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T (July 1999). "Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA". Science. 285 (5428): 727–9. doi:10.1126/science.285.5428.727. PMID 10426993.
6. Zou Y, Stastny P (December 2002). "Alternatively spliced forms of MICA and MICB lacking exon 3 in a human cell line and evidence of presence of similar RNA in human peripheral blood mononuclear cells". Immunogenetics. 54 (9): 671–4. doi:10.1016/s0198-8859(02)00518-9. PMID 12466900.
7. Universal protein resource accession number Q29983 for "MICA - MHC class I polypeptide-related sequence A precursor - Homo sapiens (Human) - MICA gene & protein" at UniProt.
8. Mistry AR, O'Callaghan CA (August 2007). "Regulation of ligands for the activating receptor NKG2D". Immunology. 121 (4): 439–47. doi:10.1111/j.1365-2567.2007.02652.x. PMC 2265965. PMID 17614877.
9. Ramachandran D, Schürmann P, Mao Q, Wang Y, Bretschneider LM, Speith LM, Hülse F, Enßen J, Bousset K, Jentschke M, Böhmer G, Strauß HG, Hirchenhain C, Schmidmayr M, Tarbiat J, Runnebaum I, Dürst M, Hein A, Koch M, Ruebner M, Ekici A, Beckmann MW, Fasching PA, Luyten A, Petry KU, Hillemanns P, Dörk T (2020). "Association of genomic variants at the Human Leukocyte Antigen locus with cervical cancer risk, HPV status, and gene expression levels". International Journal of Cancer. 147 (9): 2458–2468. doi:10.1002/ijc.33171. PMID 32580243.
10. Trinh, Thu Le; Kandell, Wendy M.; Donatelli, Sarah S.; Tu, Nhan; Tejera, Melba M.; Gilvary, Danielle L.; Eksioglu, Erika A.; Burnette, Alexis; Adams, William A. (2019-01-17). "Immune evasion by TGFβ-induced miR-183 repression of MICA/B expression in human lung tumor cells". OncoImmunology. 8 (4): e1557372. doi:10.1080/2162402x.2018.1557372. ISSN 2162-402X. PMC 6422376. PMID 30906652.
11. Ghadially H, Brown L, Lloyd C, Lewis L, Lewis A, Dillon J, Sainson R, Jovanovic J, Tigue NJ, Bannister D, Bamber L, Valge-Archer V, Wilkinson RW (April 2017). "MHC class I chain-related protein A and B (MICA and MICB) are predominantly expressed intracellularly in tumour and normal tissue". British Journal of Cancer. 116 (9): 1208–1217. doi:10.1038/bjc.2017.79. PMC 5418453. PMID 28334733.
12. Song P, Zhao Q, Zou M (2020). "Targeting senescent cells to attenuate cardiovascular disease progression". Ageing Research Reviews. 60: 101072. doi:10.1016/j.arr.2020.101072. PMC 7263313. PMID 32298812.
13. Ferrari de Andrade L, Tay RE, Pan D, Luoma AM, Ito Y, Badrinath S, Tsoucas D, Franz B, May KF, Harvey CJ, Kobold S, Pyrdol JW, Yoon C, Yuan GC, Hodi FS, Dranoff G, Wucherpfennig KW (March 2018). "Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity". Science. 359 (6383): 1537–1542. doi:10.1126/science.aao0505. PMC 6626532. PMID 29599246.
14. Li JJ, Pan K, Gu MF, Chen MS, Zhao JJ, Wang H, Liang XT, Sun JC, Xia JC (March 2013). "Prognostic value of soluble MICA levels in the serum of patients with advanced hepatocellular carcinoma". Chinese Journal of Cancer. 32 (3): 141–8. doi:10.5732/cjc.012.10025. PMC 3845598. PMID 22704489.

Further reading

• Klein J, O'hUigin C (July 1994). "The conundrum of nonclassical major histocompatibility complex genes". Proceedings of the National Academy of Sciences of the United States of America. 91 (14): 6251–2. doi:10.1073/pnas.91.14.6251. PMC 44177. PMID 8022769.
• Bahram S, Spies T (June 1996). "The MIC gene family". Research in Immunology. 147 (5): 328–33. doi:10.1016/0923-2494(96)89646-5. PMID 8876061.
• Blumberg RS (February 1998). "Current concepts in mucosal immunity. II. One size fits all: nonclassical MHC molecules fulfill multiple roles in epithelial cell function". The American Journal of Physiology. 274 (2 Pt 1): G227–31. doi:10.1152/ajpgi.1998.274.2.G227. PMID 9486173.